The retina mediates various subconscious, photoadaptive responses to light, including pupil constriction, acute enhancement of alertness, regulating hormone secretion from the brain, and synchronizing the body clock to the light/dark cycle. Inadequate or mistimed induction of these responses, such as occurs in shift workers or the blind, can lead to jet lag symptoms, winter depression, sleep disorders, headache, and even breast and prostate cancer. Retinal input to the subconscious visual system is mediated by the intrinsically photosensitive retinal ganglion cells (ipRGCs), which generate intrinsic, melanopsin-based light responses as well as extrinsic, rod/cone-driven photoresponses. These neurons were discovered recently and much remains to be learned about how they respond to different kinds of light, and how they interact with other cells in the retina. This application's long-term objective is to fill both of these knowledge gaps and use this knowledge to help develop lighting technologies that promote health and productivity, light therapies for winter depression, better diagnostic tests for eye disorders, and medical innovations that ameliorate conditions of the visually impaired. This grant proposal consists of three Specific Aims. In aim 1, whole-cell recordings will be made from ipRGCs identified using two-photon microscopy, and various pharmacological tools will be used to dissect the molecular and cellular mechanisms underlying these ganglion cells' rod/cone-driven responses to light. In aim 2, whole-cell recording, immunohistochemistry and confocal imaging will be used to identify retinal amacrine cells that receive input from ipRGCs, characterize their light-evoked responses, and determine their potential physiological functions. Aim 3 will use multielectrode-array recording, pharmacological manipulation and behavioral assays to determine the role of the retinal pigment epithelium (RPE) in the generation of ipRGCs' melanopsin-based light responses. The RPE is known to be crucial for the photosensitivity of the classical photoreceptors but their importance for ganglion-cell photoreceptors has not been fully investigated.